tbuckley/cabot-search huggingface dataset:
Cell‐Laden Gradient Microgel Suspensions for Spatial Control of Differentiation During Biofabrication
Authors: Thomas G. Molley, Tzong‐tyng Hung, Kristopher A. Kilian
Journal: Advanced Healthcare Materials (2022)

During tissue development, stem and progenitor cells form functional tissue with high cellular diversity and intricate micro- and macro-architecture. Current approaches have attempted to replicate this process with materials cues or through spontaneous cell self-organization. However, cell-directed and materials-directed organization are required simultaneously to achieve biomimetic structure and function. Here, it is shown how integrating live adipose derived stem cells with gradient microgel suspensions steers divergent differentiation outcomes. Microgel matrices composed of small particles are found to promote adipogenic differentiation, while larger particles fostered increased cell spreading and osteogenic differentiation. Tuning the matrix formulation demonstrates that early cell adhesion and spreading dictate differentiation outcome. Combining small and large microgels into gradients spatially directs proliferation and differentiation over time. After 21 days of culture, osteogenic conditions foster significant mineralization within the individual microgels, thereby providing cell-directed changes in composition and mechanics within the gradient porous scaffold. Freeform printing of high-density cell suspensions is performed across these gradients to demonstrate the potential for hierarchical tissue biofabrication. Interstitial porosity influences cell expansion from the print and microgel size guides spatial differentiation, thereby providing scope to fabricate tissue gradients at multiple scales through integrated and printed cell populations.
Phase II Study of Enzalutamide for Patients With Androgen Receptor–Positive Salivary Gland Cancers (Alliance A091404)
Authors: Alan L. Ho, Nathan R. Foster, Alex J. Zoroufy, Jordan D. Campbell, Francis Worden, Katharine Price, Douglas Adkins, Daniel W. Bowles, Hyunseok Kang, Barbara Burtness, Eric Sherman, Roscoe Morton, Luc G.T. Morris, Zaineb Nadeem, Nora Katabi, Pamela Munster, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2022)

The androgen receptor (AR) is expressed (+) in a subset of salivary gland cancers (SGCs). This phase II trial evaluated the efficacy of the antiandrogen enzalutamide in AR+ SGC.Patients with locally advanced/unresectable or metastatic AR+ SGCs were enrolled. Enzalutamide (160 mg) was given orally once daily. The primary end point was the best overall response rate per RECIST v1.1 within eight cycles. Confirmed responses in ≥ 5 of 41 patients would be considered promising. Secondary end points were progression-free survival, overall survival, and safety.Forty-six patients were enrolled; 30 (65.2%) received prior systemic therapy, including 13 (28.3%) with AR-targeted drugs. Of seven (15.2%) partial responses (PRs), only two (4.3%) were confirmed per protocol and counted toward the primary end point. Twenty-four patients (52.2%) had stable disease; 15 (32.6%) had progression of disease as best response. Twenty-six patients (56.5%) experienced tumor regression in target lesions; 18 (39.1%) had partial response/stable disease ≥ 6 months. Tumor regressions were observed in female patients (5 of 6 [83.3%]) and those who received prior AR- (6 of 13 [46.2%]) or human epidermal growth factor receptor 2-targeted therapies (5 of 8 [62.5%]). Three patients remained on treatment at data cutoff (duration, 32.2-49.8 months). The median progression-free survival was 5.6 months (95% CI, 3.7 to 7.5); the median overall survival was 17.0 months (95% CI, 11.8 to 30.0). The most common adverse events were fatigue, hypertension, hot flashes, and weight loss. Total and free testosterone levels increased by a mean of 61.2% and 48.8%, respectively, after enzalutamide.Enzalutamide demonstrated limited activity in AR+ SGC, failing to meet protocol-defined success in part because of a lack of response durability. Strategies to enhance the efficacy of antiandrogen therapy are needed.
Unleashing the potential of digital pathology data by training computer-aided diagnosis models without human annotations
Authors: Niccolò Marini, Stefano Marchesin, Sebastian Otálora, Marek Wodzinski, Alessandro Caputo, Mart van Rijthoven, Witali Aswolinskiy, John-Melle Bokhorst, Damian Podareanu, Edyta Petters, Svetla Boytcheva, Genziana Buttafuoco, Simona Vatrano, Filippo Fraggetta, Jeroen van der Laak, Maristella Agosti, Francesco Ciompi, Gianmaria Silvello, Henning Muller, Manfredo Atzori
Journal: npj Digital Medicine (2022)

The digitalization of clinical workflows and the increasing performance of deep learning algorithms are paving the way towards new methods for tackling cancer diagnosis. However, the availability of medical specialists to annotate digitized images and free-text diagnostic reports does not scale with the need for large datasets required to train robust computer-aided diagnosis methods that can target the high variability of clinical cases and data produced. This work proposes and evaluates an approach to eliminate the need for manual annotations to train computer-aided diagnosis tools in digital pathology. The approach includes two components, to automatically extract semantically meaningful concepts from diagnostic reports and use them as weak labels to train convolutional neural networks (CNNs) for histopathology diagnosis. The approach is trained (through 10-fold cross-validation) on 3'769 clinical images and reports, provided by two hospitals and tested on over 11'000 images from private and publicly available datasets. The CNN, trained with automatically generated labels, is compared with the same architecture trained with manual labels. Results show that combining text analysis and end-to-end deep neural networks allows building computer-aided diagnosis tools that reach solid performance (micro-accuracy = 0.908 at image-level) based only on existing clinical data without the need for manual annotations.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

KIR Gene Variant and PD-1 BlockadeResistance to PD-(L)1 immune checkpoint inhibitors (ICI) is common in non-small-cell lung cancer (NSCLC) patients.Trefny and colleagues have identified KIR3DS1, a genetic variation of a NK cell receptor, as a mediator of resistance to ICI in NSCLC patients.The
Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

Cross-Talk between Histone Modification and RNA Methylation N 6 -methyladenosine (m 6 A) modifications on mRNA affect diverse biological processes.Huang and colleagues show that histone H3 trimethylation at lysine 36 (H3K36me3), a marker of transcriptional elongation, dictates global m 6 A deposition.Depletion of H3K36me3 by silencing methyltransferase SETD2 or overexpressing demethylase KDM4A globally decreased m 6 A levels comparable with that of silencing any RNA methyltransferase complex (MTC) member.H3K36me3 is directly recognized by MTC member methyltransferase-like 14 (METTL14).The preponderance of H3K36me3 enrichment at the stop codon and 3'untranslated region of mRNA provides an explanation for enrichment of m 6 A at these locations.Suppression of H3K36me3-mediated m 6 A deposition by SETD2 knockdown in mouse embryonic stem cells led to expression of markers characteristic of a primitive cell state and prevented differentiation.Expert Commentary: This work demonstrates a link between histone modifications and m 6 A deposition on mRNA, the effect of which, mediates the dynamic and specific nature of m 6 A. It lays the groundwork for further elucidation of the intersection of transcription and posttranscriptional processes that regulate gene expression normally and in disease.(Image courtesy of Wikipedia Commons.)
The Recruitment-to-Inflation Ratio Is Correlated with EIT-Derived Collapse and Overdistention in COVID-19 ARDS
Authors: Tommaso Pettenuzzo, Nicolò Sella, Giulia Lorenzoni, Alvise Calore, Francesco Zarantonello, Giulio Andreatta, Alessandro De Cassai, Dario Gregori, Annalisa Boscolo, Paolo Navalesi
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

What This Study Adds to the FieldIn patients with acute respiratory distress syndrome (ARDS) secondary to coronavirus disease (COVID)-19, positive end-expiratory pressure (PEEP) selection should balance the beneficial and injurious effects of PEEP based on the potential for lung recruitment.We observed that the recruitment-to-inflation ratio (RIR) maneuver, a simple bedside method recently shown to differentiate patients based on their potential for lung recruitment, is linearly correlated with Page 2 of 13
Lung Allograft Microbiome Association with Gastroesophageal Reflux, Inflammation, and Allograft Dysfunction
Authors: Pierre H. H. Schneeberger, Chen Yang Kevin Zhang, Jessica Santilli, Bo Chen, Wei Xu, Youngho Lee, Zonelle Wijesinha, Elaine Reguera-Nuñez, Noelle Yee, Musawir Ahmed, Kristen Boonstra, Rayoun Ramendra, Courtney W. Frankel, Scott M. Palmer, Jamie L. Todd, Tereza Martinu, Bryan Coburn
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: It remains unclear how gastroesophageal reflux disease (GERD) affects allograft microbial community composition in lung transplant recipients and its impact on lung allograft inflammation and function. Objectives: Our objective was to compare the allograft microbiota in lung transplant recipients with or without clinically diagnosed GERD in the first year after transplant and assess associations between GERD, allograft microbiota, inflammation, and acute and chronic lung allograft dysfunction (ALAD and CLAD). Methods: A total of 268 BAL samples were collected from 75 lung transplant recipients at a single transplant center every 3 months after transplant for 1 year. Ten transplant recipients from a separate transplant center provided samples before and after antireflux Nissen fundoplication surgery. Microbial community composition and density were measured using 16S ribosomal RNA gene sequencing and quantitative polymerase chain reaction, respectively, and inflammatory markers and bile acids were quantified. Measurements and Main Results: We observed a range of allograft community composition with three discernible types (labeled community state types [CSTs] 1–3). Transplant recipients with GERD were more likely to have CST1, characterized by high bacterial density and relative abundance of the oropharyngeal colonizing genera Prevotella and Veillonella. GERD was associated with more frequent transitions to CST1. CST1 was associated with lower inflammatory cytokine concentrations than pathogen-dominated CST3 across the range of microbial densities observed. Cox proportional hazard models revealed associations between CST3 and the development of ALAD/CLAD. Nissen fundoplication decreased bacterial load and proinflammatory cytokines. Conclusions: GERD was associated with a high bacterial density, Prevotella- and Veillonella-dominated CST1. CST3, but not CST1 or GERD, was associated with inflammation and early development of ALAD and CLAD. Nissen fundoplication was associated with a reduction in microbial density in BAL fluid samples, especially the CST1-specific genus, Prevotella.
Creatine Kinase Is Decreased in Childhood Asthma
Authors: Stefano Guerra, Julie G. Ledford, Erik Melén, Iris Lavi, Anne-Elie Carsin, Debra A. Stern, Jing Zhai, Marta Vidal, Mariona Bustamante, Kenneth J. Addison, Renata G. Vallecillo, Dean Billheimer, Gerard H. Koppelman, Judith Garcia-Aymerich, Nathanaël Lemonnier, Montserrat Fitó, Carlota Dobaño, Simon Kebede Merid, Inger Kull, Rosemary R. C. McEachan, John Wright, Leda Chatzi, Manolis Kogevinas, Daniela Porta, Silvia Narduzzi, Ferran Ballester, Ana Esplugues, Carlos Zabaleta, Amaia Irizar, Jordi Sunyer, Marilyn Halonen, Jean Bousquet, Fernando D. Martinez, Josep M. Anto
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications.
Microbiota and lung cancer
Authors: Taichiro Goto
Journal: Seminars in Cancer Biology (2022)

Until recently, bacteria have been studied in terms of their roles in infectious diseases and mainly by using isolation and culture methods. However, in practice, many bacteria existing on the earth are difficult to isolate and culture, and thus only a limited number of them have been studied to date. On the other hand, in 2005, the next-generation sequencing technology became generally available, and since then genomic analysis of bacterial flora has become widespread. As a result, it has been revealed that the lower respiratory tract, which was previously thought to be sterile, in fact has bacterial flora (a microbiome) with a high level of biodiversity. In addition, it has been found that various diseases develop and worsen depending on the balance of the bacterial flora, and in recent years, a relationship has been established between various disorders. Recent research on cancer-associated microbial communities has elucidated the reciprocal interactions among bacteria, tumors and immune cells, the bacterial pathways associated with induction of oncogenesis, and their translational significance. Nevertheless, despite the increasing evidence showing that dysbiosis is associated with lung oncogenesis, the detailed mechanisms remain to be fully elucidated. Microorganisms seem to trigger tumor initiation and progression, presumably through the production of bacterio-toxins and other pro-inflammatory factors. The purpose of this review is to present a context for the basic mechanisms and molecular functions of the airway microbiome in oncogenesis, in an effort to prevent cancer by strategies utilizing the airway microbiota, as well as summarizing the mechanisms wherein the microbiome acts as a modulator of immunotherapies in lung cancer.
Response to ‘British Association of Dermatologists guidelines for the management of adults with basal cell carcinoma 2021’: vismodegib and indications for its use
Authors: Isla Shariatmadari, Paolo Matteucci, Alan Barreda, Lorcan O’Toole
Journal: British Journal of Dermatology (2022)

Dear Editor, The latest British Association of Dermatologists guidelines1 for the management of basal cell carcinoma (BCC) have once again established a robust framework, highlighting advances in the management of the most common skin cancer in the UK. Inclusion of the novel biologic drug vismodegib offers a unique opportunity for a subgroup of the population who have developed ‘advanced BCC’ and for patients with the genodermatosis Gorlin syndrome.1 Treatment options for locally advanced BCC (laBCC) and metastatic BCC (mBCC) include surgery, radiotherapy and, in rare selected cases, cytotoxic chemotherapy. When these options are not appropriate, best supportive care is advised. Up until its withdrawal from the Cancer Drugs Fund (CDF) in 2017,2 vismodegib offered a hopeful therapeutic option for these patients. Recommendation 14 of the new guidelines offers vismodegib ‘as a treatment option to adults with advanced BCC who are unsuitable for Mohs micrographic surgery, standard surgical excision or radiotherapy, including patients with Gorlin syndrome, following discussion at an MDT (multidisciplinary team).’1 Unfortunately, vismodegib does not have National Institute for Health and Care Excellence (NICE) or CDF approval for these indications. In view of this, we feel the guidelines should provide further clarification on the use of this novel drug.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

Targeting Oxidative Phosphorylation in Melanoma Brain MetastasesBrain metastases frequently occur in patients with metastatic melanoma and remain difficult to treat.Fischer and colleagues undertook a comprehensive molecular profiling of melanoma brain metastases (MBM) and matched extracranial metastases (ECM).Although genetic alterations were not significantly different between MBMs and ECMs, MBMs had a significantly lower immune infiltrate than ECMs and had higher levels of oxidative phosphorylation (OXPHOS).Utilizing patient samples and in vivo models, in which they compared intracranial versus subcutaneous tumors, they found that oxidative phosphorylation was induced across multiple models in a brain-specific manner.Remarkably, use of the OXPHOS inhibitor IACS-010759 was effective against intracranial tumors but not primary tumors in both immunocompromised and immunocompetent models.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

Increased SPINK1 levels associate with poor clinical outcome and represent the second-largest molecular subtype of prostate cancer. Bhatia and colleagues deciphered the mechanism of SPINK1 upregulation and established a regulatory model, showing the functional interplay between SPINK1, miRNA-338-5p/miRNA-421 and EZH2. In this study, the authors show that overexpression of miRNA-338-5p/miRNA-421 in SPINK1-positive cancer cells attenuates its oncogenic properties, tumorigenesis, and metastases. In agreement, SPINK1-postive prostate cancer patients show epigenetic silencing of miRNA-338-5p/miRNA-421 due to increased levels of EZH2. This study opens avenues for the use of epigenetic drugs or synthetic mimics of miRNA-338-5p/miRNA-421 as an adjuvant therapy for SPINK1-positive malignancies.Fibroblast growth factor receptors (FGFR), in their function as upstream tyrosine kinases activating the MAPK and the PI3K signaling pathways, can regulate cellular growth and have established roles in human tumorigenesis. In that setting, increased kinase signaling can be brought about by a variety of genetic alterations which can be detected in patient tumor samples, identifying those patients most likely to benefit from FGFR-directed therapy. In the present phase I trial, Voss and colleagues investigate the safety and efficacy of Debio 1347, a highly selective orally available FGFR 1-3 inhibitor, in a target population of patients that screened positive for harboring activating FGFR1-3 alterations in their tumors. This approach proved to be feasible with promising tolerability and efficacy results.Because of the development of resistance and high-relapse rates with currently available therapies, mixed-lineage leukemia (MLL leukemia) is frequently associated with a poor prognosis; therefore, novel therapeutic targets are urgently needed. Wang and colleagues discovered that LAMP5 is a novel autophagic suppressor, is specifically expressed in MLL leukemia, and serves as a bodyguard for fusion proteins to evade degradation. Suppressing LAMP5 expression effectively released MLL fusions from its defence system and extended survival in vivo. This effect was particularly strong when combining DOT1L inhibitors and LAMP5 knockdown. The finding highlights the potential of LAMP5 as a therapeutic target.Aberrant overexpression of stratifin (SFN) can be detected in lung adenocarcinoma from an early stage, playing a role in oncogenesis and progression. Shiba-Ishii and colleagues identify SKP1 as an SFN binding partner and demonstrate that SFN-SKP1 binding causes dysfunction of a specific ubiquitin ligase, SCFFBW7, allowing several oncoproteins to evade ubiquitination and degradation. In silico drug screening selected aprepitant and ticagrelor as potential SFN inhibitors that dose-dependently reduced SFN-SKP1 binding and tumor progression. Because SFN is widely expressed from an early stage, these drugs would be promising candidates for nonsurgical treatment of advanced and early-stage tumors.
X‐Ray Markers for Thin Film Implants
Authors: Ben J. Woodington, Lawrence Coles, Amy E. Rochford, Paul Freeman, Stephen Sawiak, Stephen J. K. O'Neill, Oren A. Scherman, Damiano G. Barone, Christopher M. Proctor, George G. Malliaras
Journal: Advanced Healthcare Materials (2022)

Implantable electronic medical devices are used in functional mapping of the brain before surgery and to deliver neuromodulation for the treatment of neurological and neuropsychiatric disorders. Their electrode arrays are assembled by hand, and this leads to bulky form factors with limited flexibility and low electrode counts. Thin film implants, made using microfabrication techniques, are emerging as an attractive alternative, as they offer dramatically improved conformability and enable high density recording and stimulation. A major limitation of these devices, however, is that they are invisible to fluoroscopy, the most common method used to monitor the insertion of implantable electrodes. Here, the development of mechanically flexible X-ray markers using bismuth- and barium-infused elastomers is reported. Their X-ray attenuation properties in human cadavers are explored and it is shown that they are biocompatible in cell cultures. It is further shown that they do not distort magnetic resonance imaging images and their integration with thin film implants is demonstrated. This work removes a key barrier for the adoption of thin film implants in brain mapping and in neuromodulation.
Deep active learning for suggestive segmentation of biomedical image stacks via optimisation of Dice scores and traced boundary length
Authors: Alessia Atzeni, Loic Peter, Eleanor Robinson, Emily Blackburn, Juri Althonayan, Daniel C. Alexander, Juan Eugenio Iglesias
Journal: Medical Image Analysis (2022)

Manual segmentation of stacks of 2D biomedical images (e.g., histology) is a time-consuming task which can be sped up with semi-automated techniques. In this article, we present a suggestive deep active learning framework that seeks to minimise the annotation effort required to achieve a certain level of accuracy when labelling such a stack. The framework suggests, at every iteration, a specific region of interest (ROI) in one of the images for manual delineation. Using a deep segmentation neural network and a mixed cross-entropy loss function, we propose a principled strategy to estimate class probabilities for the whole stack, conditioned on heterogeneous partial segmentations of the 2D images, as well as on weak supervision in the form of image indices that bound each ROI. Using the estimated probabilities, we propose a novel active learning criterion based on predictions for the estimated segmentation performance and delineation effort, measured with average Dice scores and total delineated boundary length, respectively, rather than common surrogates such as entropy. The query strategy suggests the ROI that is expected to maximise the ratio between performance and effort, while considering the adjacency of structures that may have already been labelled – which decrease the length of the boundary to trace. We provide quantitative results on synthetically deformed MRI scans and real histological data, showing that our framework can reduce labelling effort by up to 60–70% without compromising accuracy.
Endoscopy International Open – recently published
Journal: Endoscopy (2019)

Comment on: Association between endoscopic findings of eosinophilic esophagitis and responsiveness to proton pump inhibitorsEndosc Int Open 2019; 07(04): E433-E439DOI: 10.1055/a-0859-7276 Comment on: Preoperative endoscopic predictors of severe submucosal fibrosis in colorectal tumors undergoing endoscopic submucosal dissectionEndosc Int Open 2019; 07(04): E421-E430DOI: 10.1055/a-0848-8225 Comment on: Feasibility and safety of third-space endoscopic full-thickness resection in ex vivo and in vivo porcine modelsEndosc Int Open 2019; 07(04): E471-E476DOI: 10.1055/a-0858-2210